Immunotherapy

Abstract

A method is provided for enhancing the reactivity of a T cell toward a tumour cell which method comprises: (a) isolating a T cell which is a tumour infiltrating lymphocyte (TIL) from a patient having said tumour cell present in their body; (b) introducing a nucleic acid sequence into the TIL, which sequence is capable of inhibiting or preventing expression of an endogenous Notch ligand in the TIL; and (c) re-introducing the transfected TIL into the patient; wherein the T cell comprises a T cell receptor specific for a tumour antigen expressed by the tumour cell.

Description

[0001] The present invention relates to methods for enhancing the response of T cells to tumour cells. These methods may be used in tumour immunotherapy.BACKGROUND TO THE INVENTION[0002] Although significant advances have been made in recent years in the development of treatments for cancer, many of the resulting treatments are still based on administration of toxic compounds with consequential side-effects. As an alternative form of therapy, attempts have been made to enhance the patient's own immune response against tumours with varying degrees of success. It is not really understood how tumour cells escape recognition by the host immune system and / or inhibit an immune response. For example, it has been known for several years that a variety of immune cell-types infiltrate solid tumours in large numbers yet fail to mount an effective immunological response to the tumour. Indeed, it is possible to isolate tumour infiltrating lymphocytes which contain T cells with T cell receptors s...

AI Technical Summary

Benefits of technology

[0005] We have now found that the expression of Notch ligands is upregulated in some tumour cells. We have also shown that tumour cells that express a Notch ligand are capable of rendering T cells unresponsive to restimulation with specific antigen. Consequently, this may provide one possible means by which tumour cells may inhibit T cell responses. This conclusion is supported further by our previous results showing that upregulation of Notch ligand expression can induce immunotolerance (WO-A-98 / 20142). Thus, by preventing this mechanism operating in T cells in vivo, it may be possible to prevent tumour cells inducing immunotolerance in T cells that recognise tumour-specific antigens in the tumour cells. This would then allow the T cells to mount an immune response against the tumour cells.

[0114] Polynucleotide variants will preferably comprise codon optimised sequences. Codon optimisation is known in the art as a method of enhancing RNA stability and therefor gene expression. The redundancy of the genetic code means that several different codons may encode the same amino-acid. For example, Leucine, Arginine and Serine are each encoded by six different codons. Different organisms show preferences in their use of the different codons. Viruses such as HIV, for instance, use a large number of rare codons. By changing a nucleotide sequence such that rare codons are replaced by the corresponding commonly used mammalian codons, increased expression of the sequences in mammalian target cells can be achieved. Codon usage tables are known in the art for mammalian cells, as well as for a variety of other organisms. Preferably, at least part of the sequence is codon optimised. Even more preferably, the sequence is codon optimised in its entirety.

[0136] It may also be advantageous for the promoters to be inducible so that the levels of expression of the heterologous gene can be regulated during the life-time of the cell. Inducible means that the levels of expression obtained using the promoter can be regulated.

Problems solved by technology

Although significant advances have been made in recent years in the development of treatments for cancer, many of the resulting treatments are still based on administration of toxic compounds with consequential side-effects.

For example, it has been known for several years that a variety of immune cell-types infiltrate solid tumours in large numbers yet fail to mount an effective immunological response to the tumour.

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